Dementia and mild cognitive impairment (MCI) pose a large and increasing health and societal burden on the aging US population. New studies suggest that microvascular disease makes a substantial contribution to dementia and MCI. A few long-followed cohorts show strong associations of mid-life hypertension, diabetes, and smoking with dementia at older age in contrast to weak associations in studies of the elderly. An observational study relating dementia, MCI and cerebral changes observable on MRI to midlife vascular risk factors has the promise of suggesting dementia prevention strategies where none currently exist. Aims: The proposed ARIC Neurocognitive study (ARIC-NCS) will focus on prediction of cognitive impairment from mid-life vascular risk factors and markers through a 5 center R01 ancillary study to the large, bi-ethnic prospective ARIC cohort study. Prediction is expected to be particularly strong in African-Americans and persons whose dementia or MCI is diagnosed as vascular or accompanied by MRI cerebrovascular signs. Aims are to: 1) estimate the prevalence of dementia/MCI by race and sex in participants aged 70-89, 2) determine whether midlife vascular factors (risk factors and markers of macrovascular and microvascular disease) predict dementia, MCI and cognitive change, 3) determine whether the associations between midlife vascular factors and dementia/MCI differ by dementia/MCI subtype defined clinically or by MRI signs, 4) identify cerebral markers associated with cognitive change, including progression of MRI ischemic burden and atrophy across 3 MRI scans spanning 17 years, and 5) identify genomic regions containing susceptibility loci for cognitive decline, using 106 SNPs spanning the genome. Design/Methods: Prospective study of >7000 residents aged 70-89 in 4 US communities adding a 24-year follow-up evaluation with detailed neurocognitive assessment, retinal photography, lab assays and medical record review to 4 previous exams (1987-1999) which included midlife cognitive testing. Two thousand dementia and MCI cases and controls will undergo cerebral MRI with central measurement of cerebrovascular signs and brain volumes. ARIC is uniquely situated for this research since predictors already measured include macrovascular (carotid thickness, plaque and distensibility, peripheral artery disease) and microvascular markers (retinal arteriolar narrowing and nicking, retinal hemorrhage, exudates, and microaneurysms, microalbuminuria), cardiovascular events, hemostatic factors in 5 pathways, apoE, 106 SNPs across the genome, all major cardiovascular risk factors, and in many participants, one or two prior cerebral MRI exams. Implications: Longitudinal observational study of midlife vascular risk factors for cognitive and cerebral changes in the ARIC cohort will elucidate factors underlying ethnic disparities in dementia burden and provide the scientific basis for prevention strategies by identifying vascular therapeutic targets, optimal timing for interventions and useful intermediate outcomes. PUBLIC HEALTH RELEVANCE: ARIC-NCS will provide the means for identifying groups at greater risk for dementia who might benefit from risk factor modification. Its public health relevance is evident given the growing magnitude of dementia and mild cognitive impairment, the realization of a strong association with vascular disease, and the reasonable assumption that the risk of dementia and mild cognitive impairment, like strokes, can be substantially reduced by risk factor modification.